Large-coil Parietal Repetitive Transcranial Magnetic Stimulation (rTMS) for Alzheimer Disease (AD)

Prior treatment

• Contraindication to TMS or MRI including claustrophobia, MRI-incompatible or unknown metal in body (including facial tattoos with uknown or metallic inks), surgery within 60 days, certain implants (excluding dental fillings), or previous abnormal MRI results unrelated to a potential participant's dementia.
• For the randomized stage only-has a history of prior TMS treatment (not TMS naïve)
• Alteration in cognitive-enhancement medication (or other treatment) dose within the past 2 months or active plans for dose alteration during the course of the study (previously unplanned changes that occur during the study will be examined on a case-by-case basis)
• Has started treatment with lecanemab, donanemab, or any other monoclonal antibody for Alzheimer's Disease within the past 6 months OR has a history of treatment complicated by amyloid-related imaging abnormalities (ARIA)
• Currently or within the past 2 weeks taking any of the following classes of medication:
  • Anticholinergic (e.g., tolterodine, benztropine)
  • Sedating antihistamines (e.g., diphenhydramine)
  • any drug that has significant anticholinergic or antihistaminic side effects (e.g., tricyclic antidepressant medications, mirtazapine).
  • Benzodiazepines. While not a strict rule out, this will be decided on a case-by-case basis
  • Opioid. While not a strict rule out, this will be decided on a case-by-case basis
  • Antiepileptic agents. While not a strict rule out, this will be decided on a case-by-case basis
  • Antipsychotic agents. While not a strict rule out, this will be decided on a case-by-case basis

Other illness

• Diagnosis of a dementia or cognitive disorder primarily or exclusively due to a cause other than Alzheimer's Disease
• Diagnosis of severe Dementia (CDR \> 2.0/ AA clinical stage 6) at the start of the study
• History of substance use disorder currently not in sustained remission
• History of stroke, traumatic brain injury with loss of consciousness, or other major neurologic disorder (e.g., epilepsy, Huntington's disease, Parkinson's disease)
• History of seizure disorder or family history of seizure disorder in a first-degree relative
• Poorly-controlled hypertension, cardiovascular disease, or cerebrovascular disease
• History of any other major active medical, neurologic, or psychiatric illness affecting cognition (associated with cognitive impairment) or a participant's ability to safely and meaningfully participate in the study

Other

• Unwilling or unable to provide informed consent as outlined below
• Currently pregnant or potentially pregnant
• Substance misuse within the past 6 months (excluding nicotine or caffeine)
• Non-fluent in English (not native or functionally-native, specified here for cognitive testing purposes)
• Currently enrolled in an interventional memory-enhancement study

• Agreement to participate in study and able to complete informed consent process
• Have a caregiver or study partner who can accompany them to all study visits
• Have a known alternate surrogate decision-maker (in case needed) who can be present for informed consent
• Established diagnosis of biomarker-positive (amyloid-PET, plasma or CSF amyloid ratio or phosphorylated tau) mild-moderate (clinical stages 3, 4, and 5) Alzheimer's Disease based on the 2024 Alzheimer's Association Framework
• Age 55-100 at the start of the study.
• Screening MOCA 12-25 (\< 26, \> 11)
• Screening GDS score \<6
• Either 1) treated with memory-enhancing medication (cholinesterase inhibitor or other medications or treatments) for at least 2 months, 2) failed trial with no plan to re-trial, or 3) no trial planned during the course of the study for other reasons
• No change in use of psychotropic medication (or other treatments) for the treatment of depression, anxiety, ADHD, or psychosis for 2 weeks prior to the study